Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease
- Authors
- Cooper, Oliver; SEO, HYE MYUNG; Andrabi, Shaida; Guardia-Laguarta, Cristina; Graziotto, John; Sundberg, Maria; McLean, Jesse R.; Carrillo-Reid, Luis; Xie, Zhong; Osborn, Teresia; Hargus, Gunnar; Deleidi, Michela; Lawson, Tristan; Bogetofte, Helle; Perez-Torres, Eduardo; Clark, Lorraine; Moskowitz, Carol; Mazzulli, Joseph; Chen, Li; Volpicelli-Daley, Laura; Romero, Norma; Jiang, Houbo; Uitti, Ryan J.; Huang, Zhigao; Opala, Grzegorz; Scarffe, Leslie A.; Dawson, Valina L.; Klein, Christine; Feng, Jian; Ross, Owen A.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Marder, Karen; Surmeier, D. James; Wszolek, Zbigniew K.; Przedborski, Serge; Krainc, Dimitri; Dawson, Ted M.; Isacson, Ole
- Issue Date
- Jul-2012
- Publisher
- American Association for the Advancement of Science
- Keywords
- cytology; nerve cell; Humans; Protein-Serine-Threonine Kinases; PINK1 gene; Mitochondria; Ubiquinone; pluripotent stem cell; leucine rich repeat kinase 2; proton radiation; Indoles; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; female; gene; hum
- Citation
- Science Translational Medicine, v.4, no.141, pp.1 - 14
- Indexed
- SCIE
SCOPUS
- Journal Title
- Science Translational Medicine
- Volume
- 4
- Number
- 141
- Start Page
- 1
- End Page
- 14
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/36216
- DOI
- 10.1126/scitranslmed.3003985
- ISSN
- 1946-6234
- Abstract
- Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q 10, rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.
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